Rockville, MD - The US FDA has now identified a mechanism by which the contaminant—oversulfated chondroitin sulfate—could cause the adverse reactions reported with heparin, which it says strengthens the argument that this contaminant was the culprit behind the increased rate of adverse events seen.

But regulators from China, where the contaminant has been traced to, have said they are still not convinced that it is the cause of the adverse events.

Speaking at a press conference on April 21, 2008, Dr Janet Woodcock (director of the FDA's Center for Drug Evaluation and Research) reported that FDA scientists have shown in laboratory and animal tests that oversulfated chondroitin sulfate "can increase mediators that could lead to the sort of adverse reactions seen with heparin such as hypotension. . . . This solid mechanistic link between oversulfated chondroitin sulfate and the type of adverse reactions seen strengthens considerably the hypothesis that this contaminant is responsible," she said, adding that "the story is now starting to come together."

Woodcock further reported that the contaminant has so far been found in heparin supplies in 11 countries (Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand, and the US). But increased rates of adverse events associated with this heparin have been reported so far only in the US and Germany.

Woodcock noted that low-molecular-weight heparins (LMWH) have also been tested for the presence of oversulfated chondroitin sulfate, and the contaminant has been found in some LMWH products. She said that the regulators in various countries are discussing these results and the implications for their countries, but that all LMWH products on the US market have been shown to be free of the contaminant.

In an update of heparin adverse reactions, the FDA notes that 131 reports of death after receiving heparin have been reported to the agency since January 1, 2007, 123 of which were reported this year. There have been 81 reports of deaths after heparin that included allergic symptoms or symptoms of hypotension, 78 of which were reported to the FDA in 2008. These are the events that prompted the heparin recalls.

Woodcock said: "The pattern of adverse events is the most powerful indicator [of the cause]. While there was a large increase in events from November 2007 to February 2008, the numbers of reports have returned to normal in March after the recall." The chart of reported events on the FDA website shows 1 or 2 deaths with allergic/hypotensive symptoms associated with heparin reported each month before October 2007. This rose to 10 in November, 13 in December, 21 in January, and 18 in February, but no such deaths were reported in March.

The oversulfated chondroitin sulfate has been traced to heparin active pharmaceutical ingredient (API) manufactured in China as early as 2006, which generally entered the market in 2007, Woodcock said. She added that the contaminant had been found in heparin API from 12 Chinese suppliers, but how it got into the product is still not known.

Woodcock noted that many countries worldwide are now testing their heparin products for the contaminant and that representatives from the FDA met with regulators from other countries, including China, last week to discuss the results of this testing. It emerged during that meeting that Chinese regulators, while acknowledging that the identified contaminant can be sourced to Chinese suppliers, do not accept that it is responsible for the adverse events seen in the US. "Our Chinese colleagues are skeptical that a link has been established between the contaminant and the adverse events, but we are hoping to resolve this situation in the next few weeks," Woodcock commented.

Chinese regulators have pointed out that as oversulfated chondroitin sulfate has been found in heparin in 11 countries, but adverse reactions have been reported only in the US and Germany, this suggests that this particular contaminant may not be the cause. But Woodcock noted that many people in the US who got heparin containing the contaminant also did not experience adverse reactions. "It appears to have something to do with the amount of heparin given and the speed at which the heparin is delivered. Other countries may not use bolus doses of heparin so much," she said.

In addition, in their testing, the Chinese regulators said they have found one lot of heparin associated with adverse reactions in the US that did not contain oversulfated chondroitin sulfate. But Woodcock noted that the FDA also tested this heparin lot and did find the contaminant. She pointed out that the Chinese may have used different, less sensitive tests than those used in the US.

Woodcock said the important message to be delivered was: "The heparin supply in the US is being tested and is free of this contaminant. We now have a mechanistic link, and we are confident that this contaminant does trigger the adverse events seen, so we feel the adverse reactions will now cease."

She added that while the tests now in place are effective in identifying the contaminant, it was agreed at the meeting of international regulators that better screening methods were needed in general and that more comprehensive methods to ensure purity of heparin over the long term are to be developed. It was also agreed that enhanced regulation of the supply chain for all drugs, including all source material, is needed.